Patients who suffer from an acute coronary syndrome (ACS) or undergo percutaneous intervention (PCI) are subject to dual antiplatelet therapy (consisting of Aspirin and a P2Y inhibitor) as per international recommendations. The aim is to provide a secondary prevention strategy and reduce mortality. The commonest reason for the addition of oral anticoagulation to this therapeutic strategy is the pre-existence of Atrial Fibrillation with a CHA2DS2VASC score ≥1. The combination of oral anticoagulation and DAPT is termed Triple Therapy (TT). One fifth of the patients who have ACS or PCI warrant such therapy1. Withholding oral anticoagulation to reduce bleeding risk would lead to high risk of stroke and attempts to reduce DAPT puts the patients at risk of stent thrombosis, recurrent myocardial infarction (MI) and even death2.

Due to an ever increasing elderly population the incidence of AF will continue to increase, as will the incidence of coronary artery disease and ischaemia.

Evidence for the use of Triple Therapy

Prospective data from the WOEST study is the first randomised trial using TT in patients with an indication for PCI and non-valvular AF. 573 patients, all of which had an indication for oral anticoagulation were randomised to TT (Aspirin+Clopidogrel+Warfain) or DAPT (Warfarin+Clopidogrel)3. There was a marked difference in the incidence of non-fatal bleeding between the 2 groups with 19.4% of patients taking DAPT suffering from non-fatal bleeding vs 44.4% of patients receiving TT. Interestingly DAPT was found to have a reduced number of cardiovascular events compared to the TT study population with an additional reduction in all cause mortality.

Previous retrospective data analysed by Zhao et al and Karjalainen et al suggested quite different results4,5. Both groups found that TT after stenting provided a reduction in all major cardiovascular events including that of recurrent MI and stent thrombosis. Gao et al found that patients on TT vs non-TT did not suffer from increased MACE6. In addition Goa et al found the incidence of stroke to be significantly reduced (71%) compared to non-TT patients. Zhao et al data concurred with this finding.

On could therefore deduce that TT is as effective as OAC in reducing stroke within this specific population and non-inferior to DAPT in reduction of cardiovascular end points. OAC+Clopidogrel was associated with a 30% reduction in bleeding risk as opposed to TT. On a larger scale of 188,000 patients Hansen et al showed that TT was associated with a 12% higher incidence of bleeding vs OAC+Clopidogrel. In line with limited superiority data of TT over that of DAPT (OAC+Clopidogrel) patients may be subject to higher risk of bleeding without necessarily gaining any clinical morbidity or mortality benefit.

Balancing benefit vs risk

Whilst there is conflicting evidence with regards to the superiority of TT vs DAPT in patients with ACS and concomitant non-valvular AF there is little doubt that TT significantly increases patient non-fatal bleeding risk. TT has a significantly higher bleeding risk compared to aspirin as shown in studies conducted by Lambert et al7. Of approximately 11,000 patients during a 1-year follow up patients on TT experienced a 2 fold increase in rate of hospital admission for non-fatal and fatal bleeding.

In combination with the CHA2DS2VASC scoring system patients individual bleeding risk must be assessed. The HAS BLED method is most widely used and reproducible. HAS BLED has been shown to accurately predict bleeding risk in patients receiving TT in addition to being predictive for cardiovascular and stroke events in such patients. Of note bleeding exceeds thrombotic risk with a HAD BLED SCORE OF >48.

Current Recommendations

At present the ACC and ESC recommend the use of a lower target range of Warfarin (2.0-2.5) in patients who warrant TT. It is advised that all patients that undergo PCI following ACS comply with 12 months of a P2Y inhibitor regardless of the stent used. Using such an approach reduced incidence of stent thrombosis to 1% in the first month and upto 2% in the first year9. In patients in whom the bleeding risk is too substantial a shorter duration of P2Y use can be justified. Every patient should be assessed for the risk of stent thrombosis and restenosis. The DERIVATION scoring system appears the easiest and most accurate risk assessment tool for assessing early and very late stent thrombosis. Patients with a high risk of bleeding or those on TT are recommended to have PPI, especially if there is a history of gastrointestinal bleeding.

During Primary PCI patients who are known to need TT should be assessed for use of Bivalirudin as opposed to unfractionated heparin and Glycoprotein IIb/IIIa inhibitors. The HORIZONS-AMI trial showed that Bivalirudin was associated with a lowed incidence of bleeding in patients receiving TT10. In addition the ESC currently recommends that a minimum period of 3-6months may be used in patients with high risk of bleeding on TT. OAC with a single antiplatelet agent should in such cases be continued for a period of 12 months. In patients at low risk from further myocardial infarction on e can then consider OAC as the sole therapy going forward.

Conclusion

Management of patients with ACS and concomitant non valvular AF remains to be a clinical challenge for cardiology physicians.

Very few randomized control trials provide answers to guidance with regards to whether this patient cohort benefits from TT vs DAPT involving an oral anticoagulant. Studies thus far have shown that DAPT is likely non-inferior to triple therapy after an initial period of TT and that bleeding risk is markedly reduced.

Current guidelines should be adhered to. This means that patients undergoing PCI following ACS should have duration of antiplatelet treatment for 1 year. Percutaneous intervention will require DAPT, the duration of which will be dictated by the type of stent inserted. At present, ESC guidelines would recommend a period of 1 months post PCI of TT in patients that have an indication for oral anticoagulation and a BMS inserted. One would argue that if there is a pre existing need for oral anticoagulation in patients at high risk of bleeding that BMS insertion should be first choice to allow for a shorter period of bleeding risk. In patients with DES insertion a period of 3- 6 months can be justified of TT depending on the subtype of DES. DAPT (OAC+P2Y inhibitor) is then needed for 1 year. Patients that are deemed low risk for further myocardial infarction may be able to maintain single therapy with OAC to protect from stroke after the 12-month period.